Tissue factor on cells.

Abstract

Tissue factor (TF), a cell surface glycoprotein, serves as the cellular receptor for either activated or non-activated factor VII [FVII(a)] and it is the formation of TF-FVII(a) complexes on cell surfaces which triggers the coagulation cascade in vivo. TF procoagulant functional expression on cell surfaces can be regulated by at least three distinct major mechanisms: (1) transcriptional regulation of TF gene expression; (2) cell membrane alterations in cells expressing TF; and (3) neutralization of TF-activated factor VII (FVIIa) activity by plasma inhibitors. The TF gene, which is not normally expressed in vascular cell types, can be induced by several pathophysiological stimuli, particularly those elaborated upon in inflammation and cancer. However, some of the stimuli elaborated in these pathological processes, e.g. basic fibroblast growth factor, suppress the induced expression of TF in endothelium. Not all TF molecules expressed on cell surfaces are functional even though they have the ability to bind to FVII(a). The availability of anionic phospholipids on cell membranes in the vicinity of TF and the spatial localization of TF within the cell membrane influence the functional activity of TF. Once TF-FVII(a) complexes are assembled on cell surfaces, at least two plasma inhibitors, TF pathway inhibitor and antithrombin III play an important role in regulating the TF-FVII(a) functional activity by inhibiting the activation of factor VII bound to TF and by inhibiting the catalytic activity of TF-FVIIa complexes. The availability of heparan sulphate proteoglycans with anticoagulant activity on cell surfaces plays an important role in enhancing the activity of the inhibitors. This manuscript summarizes the mechanisms by which TF functional expression on cells is regulated with a particular emphasis on the recent findings of the authors and their collaborators.